Alzheimer's disease (Alzheimer's-type dementia, AD) is a progressive neurodegenerative disease that occurs in the presenium and the senium. The major symptoms of Alzheimer's disease include memory disturbance, cognitive impairment, higher brain dysfunction (aphasia, apraxia, agnosia, and constructional apraxia), personality change, and the like. Because of such symptoms, Alzheimer's disease does not only degrade the quality of life of the patient him/herself but also seriously affects the lives of people around the patient such as his/her family. Moreover, the number of patients is steadily increasing along with the aging of the population. Hence, Alzheimer's disease has become a grave problem of the modern society worldwide.
For this reason, Alzheimer's disease has been energetically studied, and it has been revealed that, for example, Alzheimer's disease is neuropathologically characterized also by the deposition of senile plaques and the deposition of the neurofibrillary tangles (the entanglement of neurofibrills and paired helical filament (PHF)). It is considered that the deposition of these structures causes neurologic dysfunction and neuronal cell death (deficit of neurons) involved in the above-described symptoms.
In addition, it has been revealed that the senile plaques are structures generated by polypeptides having approximately 40 amino acids, which are referred to as amyloid β (Aβ), aggregating and being deposited outside neurons in a high density. Moreover, the neurofibrillary tangles have also been revealed to be structures generated by tau, which is a microtubule-associated protein, being phosphorylated to be dissociated from microtubules, which form the cytoskeletons, and being polymerized together.
As described above, regarding the pathogenesis and pathogenic mechanism of Alzheimer's disease, a mechanism considered as being most likely is that Aβ is aggregated (amyloid lesion) and this aggregation promotes the phosphorylation and polymerization of tau (tau lesion), eventually leading to the neuronal cell death (amyloid cascade hypothesis); however, the pathogenic mechanism and so on of Alzheimer's disease have not been found out yet. For this reason, the current situation is that no useful target molecules have been discovered in the development of a method for treating this disease.
By the way, as one of the non-histone chromatin-associated proteins involved in the structural maintenance and transcriptional regulation of DNA, an HMGB1 (High Mobility Group Box 1) protein is known. In addition, this HMGB1 has recently attracted attention not only for such an intranuclear function but also for its functioning as so-called DAMPs (damage-associated molecular patterns) when HMGB1 is released out of a cell due to the necrosis of the cell or is actively secreted out of a cell in vascular inflammatory signal response. Moreover, HMGB1 has also been reported to suppress phagocytosis by microglia. Since the aggregation of Aβ is removed by this phagocytosis, it has been suggested that HMGB1 is involved in lesions of Alzheimer's disease and the like (PTLs 1 and 2). However, as described above, the current situation is that Alzheimer's disease has not been understood yet including its pathogenic mechanism, and its curative agent has not been available yet.